The former ERC starting grant project SmallVesselMRI (#337333), yielded 7 Tesla (7 Tesla) MRI methods to directly visualize diagnostically relevant vascular parameters related to cerebral small vessel disease (SVD) in small perforating vessels. These parameters include blood flow velocity pulsatility, which informs on vessel stiffness and could be a marker to evaluate vascular dysfunction before the development of irreversible macroscopic brain damage associated with SVD. The current proof-of-concept project entitled ‘TRIAL-READY SMALL VESSEL MRI MARKERS (SELMA) aimed to make these vascular parameters suitable for assessing treatment effects of pharmacological agents during phase II/III clinical trials, by fulfilling the following requirements: 1) Availability on widely used, clinical scanners (3 Tesla), 2) fast, automated extraction of the markers from the images, 3) known reproducibility (essential for power calculation in trials), 4) proof-of-concept in assessing effect of a drug that affects the microvasculature.
The SELMA project reached all its goals successfully. The 7 Tesla MRI method was successfully implemented on 3 Tesla MRI and software was written for fast and automated extraction of the pulsatility index from the images. The only user input required is a visual check of the image quality and outlining of a region of interest. A comparative study was performed which showed that it is possible to measure cerebral perforating artery flow velocity and pulsatility at 3 Tesla MRI, although an approximately fivefold sample size is needed at 3 Tesla relative to 7 Tesla MRI for a given effect size. Besides, systematic measurement errors require the measurements to be performed with equal scanner field strength and protocol to allow comparison between (patient) groups. Test-retest reliability assessment with repositioning of the subjects, showed that the relative uncertainty (defined as the coefficient of repeatability) in the measured velocity pulsatility index is 75% at 3 Tesla MRI. We performed a proof-of-concept study in patients with pseudoxanthoma elasticum who participated in a trial testing treatment with etidronate (n=9) vs. placebo (n=8). In the group treated with etidronate, a different mean blood flow velocity was found after treatment, but no effect on the pulsatility index was found. These findings suggest that small vessel function was altered after one year treatment in the patients, and that this drug effect can be measured on 3 Tesla MRI with the tools developed in this SELMA project.
Two challenges hampers commercialization of this marker in its current form. First, the systematic, scanner-dependent measurement errors limit the use of the pulsatility index to single center studies. Second, more patient studies are needed to learn how blood flow pulsatility relates to SVD and can be used as marker of this disease. To accelerate the acceptance of pulsatility measurements in small vessels in clinical research of SVD, we made the analysis tool publically available (
https://github.com/StanleyPham/SELMAGitHub(opens in new window)). Wider use of the marker will also stimulate further technical developments that address the systematic measurement errors.
